In mice, the Bcg/Nramp1 gene of the chromosome1,
has been implicated in natural resistance or susceptibility to infection with
several intramacrophage microorganisms. Functional studies of Bcg/Nramp1
congenic macrophages have shown that this gene has many pleiotropic effects on
macrophage activation and function. Although a specific role of Bcg/Nramp1
in the control of pleiotropic effects has not been defined yet, several
observations propose unifying hypothesis for its complex role: metal ion
transport is primary function of the Bcg/Nramp1 gene, the availability of
metal ions as cofactors for many proteins results from this primary function and,
in turn, the effect on signal transduction results from ion-regulated expression
of cellular proteins and their functions. In the present study, we examined the
possible alterations in signal transduction pathways related to different
allelic expression of the Bcg locusin B10R (Bcgr/Nramp1r)
and B10S (Bcgs/ Nramp1s) macrophages. We
have utilized 1-DE and 2-DE immunoblot analyses and investigated phosphorylation
of proteins using either anti-phosphotyrosine antibody or antibodies recognizing
specific phospho-forms of signaling proteins. In the basal state, B10R
macrophages had a superior ability to phosporylate p38 mitogen-activated protein
kinase (MAPK) and manganese superoxide dismutase. B10S counterparts were
characterized by increased phosphorylation of Erk1/Erk2 MAPKs. The activation of
macrophages revealed higher phosphorylation of signal transducer and activator
of transcription in response to interferon gamma and a rapid decline in the
level of inhibitory B-protein induced by
lipopolysaccharide in B10R macrophages compared to B10S. Altogether, our results
demonstrate a link between allelic expression of the Bcg/Nramp1 gene and
alterations in several macrophage signaling pathways, and support the hypothesis
that the allelic expression of Bcg/Nramp1 may be functionally linked to
resistance to infectious disease and, inversely, to autoimmune disease
susceptibility.